PROJECT SUMMARY/ABSTRACT Immune evasion is a major mechanism of acute myeloid leukemia (AML) persistence, and represents a barrier for long-term clinical success. There is a critical need for improved therapies for AML since despite recent therapeutic advances, the 5-year-survival rate is still less than 30% overall. Natural killer (NK) cells represent an encouraging frontier for novel anti-cancer treatments as they have the innate ability to identify, target, and kill cancer cells without prior sensitization. Our previous studies have identified a defect in a specific population of maturing NK cells in both a murine model of AML and in AML patients. This defect appears to be mediated by the overexpression of microRNA (miR)-29b, a potential regulator of TBX21 and EOMES, two key transcription factors important for NK cell development. We believe at least part of this negative regulation is due to soluble tumor-derived signals which drive this overexpression of miR-29b in NK cells. We hypothesize that soluble ligands from leukemic blasts both directly elevate miR-29b through the export of extracellular vesicles, as well as indirectly through the activation of the aryl hydrocarbon receptor (AHR), a ligand activated transcription factor expressed in immature NK cells. We have previously shown that AHR modulates early NK cell development, and preliminary studies indicate AHR may bind to and regulate the miR-29b promoter. This preliminary work led to the following specific aims: 1) To determine the mechanism(s) and impact of NK cell dysregulation of miR-29b in AML. 2) To determine the impact of blocking the aryl hydrocarbon receptor pathway on NK cell function in vivo. These aims are important for both defining how AML is able to evade innate immunity, and identifying potential targets for therapeutic intervention. The studies outlined in this proposal will form a solid foundation from which the PI will begin building a successful independent career in the field of tumor immunology and advancing the knowledge and treatment options of cancer. To achieve these goals, the PI has established an extensive network of collaborators and world-class mentors to guide her through the early stages of her career. Additionally, the PI has outlined numerous meetings, courses and educational enrichment activities supported by her institution to further increase the success and effectiveness of her career. Together, the aforementioned activities with this research proposal will provide the framework for her transition into an independent environment and long-term career goals of translating these discoveries to novel therapeutics to improve patient outcomes.